The present invention relates to methods for diagnosing a bipolar disorder and screening for therapeutic compounds for treating or preventing a bipolar disorder.
Bipolar disorder (BD) is a major psychiatric disease characterized by episodes of depression and mania or hypomania interspaced by periods of euthymia. With a typical age of onset in late adolescence or early adulthood, BD is a major health problem that involves continuous monitoring and often lifelong treatment, and places a substantial economic burden on healthcare systems and society. A recent Swedish resource use study estimated the average annual cost to 28,011 euro/year/patients, and a 2009 US-study estimated the direct and indirect costs of BD to be 151 billion dollars.
Although a number of studies of families and twins show the significance of genetic factors affecting susceptibility to BD, the precise pathogenesis of BD is not well understood. BD may be a neuroinflammatory or neurodegenerative disorder, in which relapses are toxic, indicating the utility of early detection to prevent an otherwise negative prognosis. However, accumulating evidence suggests that mitochondrial dysfunction plays a key role in the pathogenesis of BD.
Metabolomics is the profiling of small molecule metabolites and provides the potential to characterize specific metabolic phenotypes associated with a disease. Metabolomics has an advantage over other “omics” techniques in that it directly samples the metabolic changes in an organism and integrates information from changes at the gene, transcript, and protein levels, as well as posttranslational modifications. Metabolomics analysis of postmortem brain samples from BD patients and controls have been reported. Tissue concentration of small molecules, such as amino acids, in brain samples is known to be significantly affected by postmortem interval (PMI). Therefore, metabolomic analyses using postmortem brain samples might not be useful for determination of biomarkers. Cerebrospinal fluid (CSF) is a highly relevant sampling substrate for the in vivo study of brain disorders as it reflects the metabolic status and the biochemistry of the brain. Metabolomic profiles of CSF in patients and controls therefore have the potential to reveal protein differences linked to the pathogenesis of BD that might have value as biomarkers.
Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) is a state-of-the-art metabolome analysis technique. The advantages of CE-TOFMS analysis include extremely high resolution, versatility, and ability to simultaneously quantify virtually all the charged low-molecular-weight compounds in a sample. Two studies using this technique have shown robust changes in four molecules (arginine, taurine, 5-oxoproline, and lactic acid) in the plasma of autism spectrum disorders, and significant changes in the five molecules (creatine, betaine, nonanoic acid, benzoic acid, and perillic acid) in the plasma of first-episode, medicated patients with schizophrenia. However, there are no reports using this technique in CSF samples from BD patients.
Accordingly, there is a need for methods of diagnosing bipolar disorders and identifying compounds having potential efficacy against bipolar disorders.